P744: UNBALANCED TRANSLOCATION DER(1;7)(Q10;P10) AS A DISTINCT SUBTYPE IN MYELODYSPLASTIC SYNDROMES
Authors: R. Okuda, Y. Ochi, K. Chonabayashi, N. Hiramoto, M. Sanada, H. Handa, S. Kasahara, S. Sato, N. Kanemura, T. Kitano, M. Watanabe, W. Kern, M. Creignou, Y. Shiraishi, M. Watanabe, K. Usuki, S. Imashuku, E. Hellstrom-Lindberg, T. Haferlach, S. Chiba, N. Sezaki, L.-Y. Shih, Y. Miyazaki, Y. Yoshida, T. Ishikawa, K. Ohyashiki, Y. Atsuta, Y. Shiozawa, S. Miyano, H. Makishima, Y. Nannya, S. Ogawa
Journal: HemaSphere (2022)

Background: der(1;7)(q10;p10) (der(1;7)) is an unbalanced translocation between chromosomes 1 and 7 found in 1.5-6% of patients with myelodysplastic syndromes (MDS), depending on different ethnicity, where the common consequence is +1q and -7q. Previous studies have noted a higher incidence of RUNX1 mutation and better prognosis for der(1;7) cases compared to -7/del(7q) MDS cases. While previous studies have described several features of der(1;7), the understanding of der(1;7)+ MDS/AML is largely limited due to their small study size. Aims: To elucidate the clinical and genetic characteristics of der(1;7) with integrated omics analysis in a large cohort of myeloid neoplasms. Methods: We enrolled 148 cases with der(1;7) and analyzed their mutation profiles and clinical features using whole exome and/or targeted-capture sequencing of major driver genes of myeloid neoplasms and RNA sequencing. Distinct features of der(1;7) were investigated by comparing the results with those from an additional 3,238 non-der(1;7) cases with different myeloid neoplasms comprising -7/del(7q), +1q, and other cases. Results: 148 der(1;7) cases comprised 72.3% MDS, 23.7% AML, and 3.4% MDS/MPN cases. Compared to -7/del(7q) AML cases, der(1;7) AML cases were more likely to be AML with dysplasia or MDS-derived AML and therapy-related AML (84.4% vs 53.2% and 9.1% vs 1.9%, respectively) (p<0.001). Targeted-capture sequencing of der(1;7) cases revealed that 91.9% of cases harbored at least one copy number change or mutation. The frequency of genetic mutation and copy number alteration for der(1;7) cases substantially differed compared to -7/del(7q), +1q, and other cases. der(1;7) cases had frequent mutations affecting RUNX1 (37.8%), EZH2 (18.9%) and ETNK1 (18.2%), which were less common in -7/del(7q) cases (OR=5.58, OR=6.52, and OR=6.23, respectively). By contrast, TP53 mutations were less frequent in der(1;7) cases (OR=0.021). Copy number analysis revealed a frequent co-occurrence of +8 and del(20q) with der(1;7) cases (18.9% and 37.4%), while del(5q), which frequently co-occurred with del(7q), was not found in der(1;7) cases. Prognosis of der(1;7) MDS cases tended to be better than -7/del(7q) cases (HR=0.71, p=0.098), but poorer than +1q (HR=1.36, p=0.11) and others cases (HR=1.8, p<0.001). The most frequent cause of death in der(1;7) cases was infection (45.5%), followed by disease progression (36.4%). This high frequency of infection as a cause of death was unique in der(1;7) as compared to -7/del(7q) (infection 13.9% and disease progression 72.3%) and others (infection 10.8% and disease progression 76.9%). Finally, RNA-sequencing analysis between der(1;7) MDS cases and non-der(1;7) MDS cases showed unique expression profiles in der(1;7). 1,463 differentially expressed genes were identified, of which 895 were down-regulated and 573 were up-regulated. GSEA analysis of major pathways showed down-regulation of those related to cell cycles (including E2F targets), innate immunity, and TNFα signaling via NFκB. Gene ontology analysis also revealed down-regulation of cell cycle-related pathways, further supporting the significance of the down-regulated cell cycles in der(1;7) MDS cases, compared to non-der(1;7) cases. Summary/Conclusion: der(1;7)-positive MDS and AML represent a distinct subtype of myeloid neoplasms, characterized by unique patterns of co-mutations/copy-number lesions and gene expression profiles showing down-regulation of the cell-cycle pathway.